Complement is believed to play a major role in host defense against infection. In general, complement causes damage by three mechanisms. For certain targets, interaction of the complement proteins with the target cell or microorganism causes direct lysis of that microorganism or cell. In a second series of reactions, complement proteins deposited on cells or microorganisms interact with a series of specific receptors on phagocytes that aid in the phagocytic process, thus removing the pathologic cell or microorganism from the body. Complement activation also leads to the generation of a series of activation peptides that are capable of producing inflammation. In addition, complement is thought to play a major role in the afferent limb of the immune response, increasing the immunogenicity of antigens with bound complement peptides. It may also be important in eliminating clones of lymphocytes involved in the immune response to self antigens.
It is believed that the major efferent functions of complement are, in part, responsible for some of the symptomatology in autoimmune disease. In autoimmune diseases, antigens on an individual's own tissues (self antigens) within the body become immunogenic and induce an immune response, for reasons that are not fully understood. One of the mechanisms in damaging the host's cells or tissues is activation of the complement system by antibody with resulting destruction of the cells or tissues. Another mechanism is the formation of or deposition of immune complexes within tissues with the activation of complement and the production of inflammation.
There are three pathways of complement activation that have been identified: the lectin pathway, the classical pathway, and the alternative pathway (details of pathway function are published elsewhere, e.g., in The Human Complement System in Health and Disease, Volanakis and Frank (eds), Marcel Dekker, Inc. (1998)). The lectin pathway appears to be a primative pathway induced by a series of lectin like molecules, such as mannan binding lectin (MBL) These proteins bind to the surface of microorganisms with the appropriate sugar moiety on their surface and activate a series of enzymes. This in turn leads to activation of complement and the destructive process described above.
In the classical pathway, specific antibody is formed to either tissues, other body constituents, or to microorganisms. In turn, this recruits a series of complement proteins termed C1, C4, and C2, to form an enzyme capable of activating C3 and the later proteins of the complement cascade. This activation pathway leads to the above-described pathologic consequences.
The third pathway is termed the alternative pathway Here, complement proteins are capable of interacting with activators of the alternative pathway, such as microorganism surfaces. These proteins can be deposited on the surface of certain microorganisms in the absence of specific antibody. The later acting complement proteins are recruited leading to damage.
The lectin pathway is a relatively recent discovery, but the alternative and classical pathways have been studied for some years. It is believed that the alternative pathway is a philogenetically older pathway that does not have an absolute requirement of antibody to function. It would appear that the classical pathway evolved to provide a higher degree of specificity and sensitivity to the damage producing complement related steps.
Thus, antibody can target tissues for destruction. In certain autoimmune diseases, this leads to specific destruction of a patient's own tissue. The advantage of blocking the classical pathway and not the alternative pathway is that the alternative pathway provides a first line of defense against microorganisms. It is believed that because the alternative pathway does not require antibody, patients with an intact alternative pathway are relatively protected against overwhelming infection. The classical pathway, in some autoimmune diseases, is of particular importance since antibody to host tissue or various released tissue components can activate the classical pathway and initiate damage. Thus, blocking the classical pathway in some diseases may lead to specific interruption of the pathophysiologic sequence leading to tissue damage and disease. If this could be done with an alternative pathway relatively intact, it would lead to blocking of the pathophysiologic sequence, without subjecting the patient to an unacceptable risk of infection. Nonetheless, there may be situations in which blocking of the alternative pathway alone, or both the alternative and classical pathways, is preferable.
It was reported previously that intravenous immunoglobulin blocks the binding of C3 to target tissues. Subsequently, it was reported that not only is C3 binding to target tissues blocked by high levels of monomeric immunoglobulin, but C4 binding to target tissues is blocked as well. There are data that suggest that since C4 must be activated and must bind to a target before C3, it is the blocking of C4 binding that is central to classical pathway inhibition. Further research has now shown that this blockade is due to activity of the Fc fragment of the IgG.
The present invention results, at least in part, from the demonstration that peptides can be isolated from digests of the Fc fragment of IgG that retain the complement blocking activity shown in intact immunoglobulins.